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Functional and biophysical analysis of the C-terminus of the CGRP-receptor ; a family B GPCR
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Conner, Matthew, Hicks, Matthew R., Dafforn, Tim, Knowles, Timothy J., Ludwig, Christian, Staddon, Susan, Overduin, Michael, Guenther, Ulrich L., Thome, J. (Johannes), Wheatley, Mark, Dr., Poyner, David R. and Conner, Alex C. (2008) Functional and biophysical analysis of the C-terminus of the CGRP-receptor ; a family B GPCR. Biochemistry, Vol.47 (No.32). pp. 8434-8444. doi:10.1021/bi8004126 ISSN 0006-2960.
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Official URL: http://dx.doi.org/10.1021/bi8004126
Abstract
G-protein coupled receptors (GPCRs) typically have a functionally important C-terminus which, in the largest subfamily (family A), includes a membrane-parallel eighth helix. Mutations of this region are associated with several diseases. There are few C-terminal studies on the family B GPCRs and no data supporting the existence of a similar eighth helix in this second major subfamily, which has little or no sequence homology to family A GPCRs. Here we show that the C-terminus of a family B GPCR (CLR) has a disparate region from N400 to C436 required for CGRP-mediated internalization, and a proximal region of twelve residues (from G388 to W399), in a similar position to the family A eighth helix, required for receptor localization at the cell surface. A combination of circular and linear dichroism, fluorescence and modified waterLOGSY NMR spectroscopy (SALMON) demonstrated that a peptide mimetic of this domain readily forms a membrane-parallel helix anchored to the liposome by an interfacial tryptophan residue. The study reveals two key functions held within the C-terminus of a family B GPCR and presents support for an eighth helical region with striking topological similarity to the nonhomologous family A receptor. This helix structure appears to be found in most other family B GPCRs.
Item Type: | Journal Article | ||||
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Subjects: | Q Science > QC Physics Q Science > QD Chemistry Q Science > QP Physiology |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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Library of Congress Subject Headings (LCSH): | G proteins -- Receptors, Calcitonin gene-related peptide, Dichroism, Functional analysis | ||||
Journal or Publication Title: | Biochemistry | ||||
Publisher: | American Chemical Society | ||||
ISSN: | 0006-2960 | ||||
Official Date: | 12 August 2008 | ||||
Dates: |
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Volume: | Vol.47 | ||||
Number: | No.32 | ||||
Number of Pages: | 11 | ||||
Page Range: | pp. 8434-8444 | ||||
DOI: | 10.1021/bi8004126 | ||||
Status: | Peer Reviewed | ||||
Publication Status: | Published | ||||
Access rights to Published version: | Restricted or Subscription Access | ||||
Funder: | Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), European Union (EU), Engineering and Physical Sciences Research Council (EPSRC) | ||||
Grant number: | GR/T09224/01 (EPSRC) |
Data sourced from Thomson Reuters' Web of Knowledge
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